INSIGHT

VIROLOGY Pushing the envelope Primates have co-opted a viral gene to produce an envelope protein that prevents infection by the HERV-T virus and likely contributed to the extinction of this virus.

JULIA H WILDSCHUTTE AND JOHN M COFFIN

chickens (Payne et al., 1971) and mice Related research article Blanco-Melo D, (Buller et al., 1987). Now, in eLife, Daniel Gifford RJ, Bieniasz PD. 2017. Co-option of Blanco-Melo, Robert Gifford and Paul Bieniasz an endogenous retrovirus envelope for host of the Rockefeller University and MRC-University of Glasgow Centre for Virus Research report the defense in hominid ancestors. eLife 6: first example of such interference in humans e22519. doi: 10.7554/eLife.22519 (Blanco-Melo et al., 2017). When a retrovirus infects a cell it integrates a DNA copy of its own genome (called a provirus) into the host cell’s genome. Because retroviruses o counter the constant threat posed by occasionally infect germ line cells, the infection viruses, vertebrate species have evolved may lead to a provirus that is passed to off- T a variety of antiviral mechanisms. In spring, and that can sometimes become fixed in return, however, rapid mutation and turnover the population. We refer to such proviruses as rates permit viruses to swiftly evolve to evade ‘endogenous retroviruses’. Over millions of such mechanisms. This on-going ‘arms race’ years, large numbers of endogenous retroviruses between viruses and their hosts has had an have accumulated within vertebrate genomes, important role in shaping the evolution of the including humans, thus providing a ‘fossil record’ species we observe today (tenOever, 2016). of previously circulating retroviruses that covers Before a virus infects a cell, envelope proteins vast evolutionary scales. displayed on its surface must bind to a receptor While the majority of endogenous retrovirus located on the surface of the host cell. This lineages are ancient and now contain many receptor-envelope interaction is highly specific mutations, recently formed examples tend to and, in turn, determines whether the virus is able more closely resemble their infectious counter- to infect a particular cell type or species. In other parts. This similarity means that, unless it is words, in the absence of the receptor the virus harmful, an endogenous retrovirus may retain loses its ability to infect the cell. the ability to produce functional RNA and pro- In a process termed ‘receptor interference’, tein products for long periods of time. Indeed, a an envelope protein from a previous viral infec- few such endogenous retroviruses have been tion can block cell receptors, preventing infec- ‘co-opted’ to produce RNA or proteins that ben- tion by a new virus – even an unrelated one – efit the host (Ting et al., 1992; Mi et al., 2000; that also binds to that receptor (Figure 1). Stoye and Coffin, 2000). Copyright Wildschutte and Coffin. Remarkably, envelope proteins from such pre- The HERV-T lineage of endogenous retrovi- This article is distributed under the infecting retroviruses can mediate receptor ruses is an ancient member of a large group of terms of the Creative Commons interference even if they have been extinct for retroviruses called gammaretroviruses (which Attribution License, which permits millions of years (Boeke and Stoye, 1997). To includes leukemia viruses that affect cats and unrestricted use and redistribution provided that the original author and date, clear examples of such interference have rodents). As detailed by Blanco-Melo et al., the source are credited. been limited to animal models, including HERV-T ancestor appears to have first invaded

Wildschutte and Coffin. eLife 2017;6:e26397. DOI: 10.7554/eLife.26397 1 of 3 Insight Virology Pushing the envelope

Figure 1. Co-option of a viral protein for receptor interference. Left: Cells expressing MCT1 (blue), which is the receptor for a retrovirus called HERV-T, are susceptible to infection from a virus that encodes a surface envelope protein produced by an ancestral form of HERV-T (red). Right: Our genome contains proviruses – copies of the DNA of ancient retroviruses, including HERV-T. Blanco-Melo et al. found that human cells can still produce envelope proteins from their copy of the env gene of the HERV-T provirus. These envelope proteins protect the cells from the resurrected virus by blocking the MCT1 receptors directly, or through the degradation of the resulting receptor-protein complex.

primate germlines about 43 to 32 million years had the version of env that is found in the host ago, with the last invasion happening around 8 were resistant to infection. Blanco-Melo et al. million years ago. Why did this lineage become then demonstrated that the product of the host- extinct? Blanco-Melo et al. used an approach maintained env gene is able to block infection known as ‘paleovirology’ (Emerman and Malik, by viruses that encode the ancestral env gene by 2010) to begin to investigate this question. depleting the receptor they identified as MCT-1 By assessing the distribution of fossilized (monocarboxylate transporter-1) from the sur- endogenous retroviruses among modern primate face of the host cell. The results imply that the species, Blanco-Melo et al. identified a single HERV-T env gene in the host was co-opted and HERV-T locus that appeared in the germline selected for antiviral protection through recep- approximately 19 to 7 million years ago, whose tor interference. envelope (env) gene, remarkably, has retained The work from Blanco-Melo et al. highlights the ability to be translated. As other genes in the how endogenous retroviruses can act as raw same provirus have been inactivated by muta- material for potential use by the host in the tions, this observation strongly suggests that this host-virus arms race. This result raises the issue env gene has been selectively retained. However, of the extent to which the co-option of endoge- its product cannot perform any ‘normal’ retroviral nous retrovirus coding material for antiviral pro- functions. Why, then, should this gene have been tection is widespread among vertebrates. Could so clearly preserved throughout evolution? such maintained env genes have contributed to Blanco-Melo et al. reconstructed an ancestral the apparent extinction of other infectious retro- HERV-T sequence from the HERV-T proviruses viruses in the lineage leading to contemporary found in the genomes of modern humans and humans? We are eager to see whether the other primates. A variety of cell lines could be HERV-T picture represents a predictable pattern infected by reconstructed viruses that encoded among endogenous retroviruses in other verte- the ancestral env product, but those cells that brate lineages.

Wildschutte and Coffin. eLife 2017;6:e26397. DOI: 10.7554/eLife.26397 2 of 3 Insight Virology Pushing the envelope

Julia H Wildschutte is in the Department of gene linked to the rmcf locus. Journal of Virology 61: Biological Sciences, Bowling Green State 29–34. PMID: 3023705 University, Bowling Green, United States Emerman M, Malik HS. 2010. Paleovirology–modern consequences of ancient viruses. PLoS Biology 8: http://orcid.org/0000-0002-6096-750X e1000301. doi: 10.1371/journal.pbio.1000301, John M Coffin is in the Department of PMID: 20161719 Molecular Biology and Microbiology, Tufts Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, University, Boston, United States LaVallie E, Tang XY, Edouard P, Howes S, Keith JC, [email protected] McCoy JM. 2000. Syncytin is a captive retroviral envelope protein involved in human placental http://orcid.org/0000-0003-3856-762X morphogenesis. Nature 403:785–789. doi: 10.1038/ Competing interests: The authors declare that 35001608, PMID: 10693809 no competing interests exist. Payne LN, Pani PK, Weiss RA. 1971. A dominant epistatic gene which inhibits cellular susceptibility to Published 13 April 2017 RSV(RAV-O). Journal of General Virology 13:455–462. doi: 10.1099/0022-1317-13-3-455, PMID: 4334301 Stoye JP, Coffin JM. 2000. A provirus put to work. References Nature 403:715–717. doi: 10.1038/35001700, Blanco-Melo D, Gifford RJ, Bieniasz PD. 2017. Co- PMID: 10693785 option of an endogenous retrovirus envelope for host tenOever BR. 2016. The evolution of antiviral defense defense in hominid ancestors. eLife 6:e22519. doi: 10. systems. Cell Host & Microbe 19:142–149. doi: 10. 7554/eLife.22519 1016/j.chom.2016.01.006, PMID: 26867173 Boeke JD, Stoye JP. 1997. Retrotransposons, Ting CN, Rosenberg MP, Snow CM, Samuelson LC, Endogenous Retroviruses, and the Evolution of Meisler MH. 1992. Endogenous retroviral sequences Retroelements. In: Coffin J. M, Hughes S. H, Varmus H. are required for tissue-specific expression of a human E (Eds). Retroviruses. Cold Spring Harbor, NY: Cold salivary amylase gene. Genes & Development 6:1457– Spring Harbor Laboratory Press. 1465. doi: 10.1101/gad.6.8.1457, PMID: 1379564 Buller RS, Ahmed A, Portis JL. 1987. Identification of two forms of an endogenous murine retroviral env

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